title: Ischemic and inflammatory lung impairment by extracorporeal circulation: effect of PARP-inhibition by INO1001.
abstract: OBJECTIVE
  Among the complications after cardiac surgery the development of postoperative pulmonary distress is a serious problem. Typically, the patients leave the operating theatre with good blood gas values and O(2)-saturation, but develop their respiratory problems within the next hours/days. We investigated whether extracorporeal circulation may induce biochemical and histological changes in the lungs which may help to explain this development.
  
  
  METHODS
  Piglets (6-10 kg) were anaesthetized using isoflurane and underwent extracorporeal circulation (ECC) with hypothermic (25-28 degrees C) cardioplegic arrest for 90 min followed by 3h reperfusion. An additional group received a poly(ADP-ribose) polymerase (PARP)-Inhibitor, INO1001. Cardiopulmonary monitoring was performed during the whole procedure. Finally, lungs were explanted and investigated by histomorphometry and immunohistology for heat shock protein HSP70 (indicator for cellular damage) and TNFalpha in comparison to normal piglets without ECC.
  
  
  RESULTS
  Histologically we found significant swelling of the type I alveocytes (thickness increased from 2.4 to 3.2 microm), interstitial oedema, intra-alveolar erythrocyte (4.8 versus 0.4 erythrocytes/alveole) and granulocyte accumulation and fibrinous exudates. There was a significant up-regulation of TNFalpha and of the cellular repair enzyme HSP70, while in control piglets only minimal levels were observed. INO1001 significantly reduced ECC-induced elevation in TNFalpha and in HSP70. Despite the dramatic changes after heart-lung-machine (HLM), blood gases and gas transport were almost not affected at that time.
  
  
  CONCLUSIONS
  ECC can lead to early significant histological and histochemical changes which have similarities with a beginning early stage shock lung, although - at 3h reperfusion - gas transport is still sufficient. INO1001 can partially antagonize these changes.
authors.affiliation: Clinic for Cardiac Surgery, Heart Centre Leipzig, Struempellstr. 39, 04289 Leipzig, Germany. dhes@medizin.uni-leipzig.de
authors.forename: S
authors.initials: S
authors.lastname: Dhein
authors.forename: N
authors.initials: N
authors.lastname: Krause
authors.forename: C
authors.initials: C
authors.lastname: Ullmann
authors.forename: A
authors.initials: A
authors.lastname: Flister
authors.forename: S
authors.initials: S
authors.lastname: Lehmann
authors.forename: P
authors.initials: P
authors.lastname: Muth
authors.forename: T
authors.initials: T
authors.lastname: Walther
authors.forename: M
authors.initials: M
authors.lastname: Kostelka
authors.forename: F W
authors.initials: FW
authors.lastname: Mohr
mesh_terms: D000818:Animals; D005112:Extracorporeal Circulation / Q000009:adverse effects*; D006098:Granulocytes / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis / Q000096:biosynthesis; D007211:Indoles / Q000494:pharmacology*; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008171:Lung Diseases / Q000188:drug therapy* / Q000209:etiology*; D010101:Oxygen Consumption / Q000502:physiology; D011014:Pneumonia / Q000188:drug therapy* / Q000473:pathology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011650:Pulmonary Alveoli / Q000473:pathology; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis
chemical_list: D018840:HSP70 Heat-Shock Proteins; C491685:INO 1001; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014409:Tumor Necrosis Factor-alpha